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Iron metabolism dictates NK cell function

Grählert, Jasmin. Iron metabolism dictates NK cell function. 2019, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_13730

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Abstract

Background and rational: The ability to lyse tumor cells without prior sensitization endows NK cells with great therapeutic potential for adoptive cell therapy against various malignancies. Of particular interest are cytokine-enhanced – “trained” or “memory-like” – NK cells due to their enhanced responsiveness when reactivated. The molecular mechanisms underpinning augmented responses of cytokine-enhanced NK cells remain unknown. Cellular metabolism regulates cell proliferation and effector maturation alike, both critically important to effective and sustained adoptive cell therapy. Here we assessed how cellular metabolism relates to proliferation and effector maturation of naïve (NV) vs. cytokine-enhanced (CE) NK cells.
Results: Glycolysis was similarly induced and equally required for NV and CE NK cells to proliferate and acquire effector function. By contrast, upregulation of CD71 was a key discriminating factor between in vitro activated NV and CE NK cells, with distinctly higher cell surface expression on stimulated CE NK cells. Differential expression of CD71 translated into an increased capacity of CE NK cells to take up transferrin/iron, and was associated with higher proliferation rates. CD71-mediated iron uptake was a prerequisite for activation-induced NK cell proliferation also in vivo. In CE NK cells upregulation of the iron regulatory proteins 1 and 2 (IRP1/2) selectively created a pseudo iron deficient state. This cellular state enabled increased translation of CD71 and hence proliferation of activated CE NK cells.
Conclusions: Our data (i) identify CD71-mediated iron uptake as a metabolic checkpoint regulating NK cell proliferation, and (ii) assign a novel role to IRP1/2 through creating pseudo iron deficiency in a cell population-selective manner. Regulating CD71 in the context of pseudo iron deficiency enabled increased proliferation of CE NK cells – a concept with potentially broad relevance when aiming to improve proliferation of engineered immune cells.
Advisors:Hess, Christoph and Stern, Martin and Held, Werner
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Immunobiology (Hess C)
05 Faculty of Science > Departement Biozentrum
UniBasel Contributors:Hess, Christoph and Stern, Martin
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:13730
Thesis status:Complete
Number of Pages:1 Online-Ressource (V, 67 Blätter)
Language:English
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Last Modified:23 Oct 2020 04:30
Deposited On:22 Oct 2020 07:49

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